This proposal describes a biomarker-driven phase ll chemoprevention study for premalignant lesions (dysplasia) of the oral cavity and larynx in former smokers using an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TK1) ZD1839 and a cyclooxygenase-2 (COX-2) inhibitor Celecoxib. Each of these agents has strong single agent chemopreventive activity and a combination of these agents has demonstrated synergistic effect in preclinical studies. We hypothesize that a combination of ZDt 839 and Celecoxib can synergistically inhibit carcinogenesis by blocking EGFR-mediated mitogenic signaling and COX-2 mediated pathways in premalignant lesions in the upper aerodigestive tract of former smokers. This combined therapy may reverse the pathological phenotype of premalignant lesions in the oral cavity and larynx. To this end, we propose the following specific aims. Aim 1: To evaluate the efficacy, toxicity, and pharmacokinetics of ZD1839 plus Celecoxib for the treatment of premalignant lesions of the oral cavity and larynx in former smokers. Aim 2: To evaluate whether selected biomarkers (i.e., EGFR/phospho-EGFR, COX-2, prostaglandin E2, phospho-MAPK/ERK1/2, phospho-STAT-3, phospho-Akt, p27, VEGF, cyclin D1, and apoptosis and Ki-67) involved in EGFR-mediated signaling and COX-2 pathways are aberrantly expressed in premalignant lesions and carcinogen-exposed normal buccal mucosa in former smokers. Aim 3: To determine whether the proposed biomarkers are modulated by combined treatment with ZD1839 and Celecoxib and utilized as intermediate endpoint(s) in this chemoprevention study. Fifty patients with pathologically confirmed dysplastic premalignant Lesions of the oral cavity, and larynx will be treated with ZD1839 and Celexoxib for a total of 6 months. Repeated biopsies of the targeted premalignant lesions and cytobrush specimens from the normal buccal mucosa exposed to tobacco-carcinogen from the same patients will be evaluated for pathologic response and biomarker changes at baseline, and after 3-, 6-, and 12-months of treatment. Using biopsied tissue and cytologic specimens, we will investigate the proposed biomarkers with immunohistochemistry, immunoblotting, RT-PCR, enzyme immunoassay and apoptotic (TUNEL) assay. Biomarker changes will be correlated with cancer incidence by statistical analyses. We will also determine whether such biomarker changes can serve as intermediate endpoint(s) in this chemopreventive trial.